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The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

ABSTRACT: Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst^-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia, and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst^-/- mice because of exaggerated induction of sulfide disposal, with associated suppression of global protein persulfidation and nuclear respiratory factor 2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium-chain fatty acid oxidation in Tst^-/- mice. We reveal a critical role of TST in hepatic metabolism that has implications for sulfide donor strategies in the context of metabolic disease.

SUBMITTER: Carter RN

PROVIDER: S-EPMC8595646 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

Carter Roderick N RN Gibbins Matthew T G MTG Barrios-Llerena Martin E ME Wilkie Stephen E SE Freddolino Lydia L Libiad Marouane M Vitvitsky Victor V Emerson Barry B Le Bihan Thierry T Brice Madara M Su Huizhong H Denham Scott G SG Homer Natalie Z M NZM Mc Fadden Clare C Tailleux Anne A Faresse Nourdine N Sulpice Thierry T Briand Francois F Gillingwater Tom T Ahn Kyo Han KH Singha Subhankar S McMaster Claire C Hartley Richard C RC Staels Bart B Gray Gillian A GA Finch Andrew J AJ Selman Colin C Banerjee Ruma R Morton Nicholas M NM

Cell reports 20211101 6

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst<sup>-/-</sup> mice) exhibit high circulating sulfide, increased gluconeogenes ...[more]

PMID: 34758301

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Project description:BackgroundPerioperative inflammation is associated with poor oncologic outcomes. Regional analgesia has been shown mitigate some of these inflammatory changes and be associated with better oncologic outcomes in patients with hepatic malignancies. The mechanism for this effect, however, remains unclear. The authors sought to compare systemic biomarker concentrations in a comprehensive and oncologically relevant panel in the perioperative setting between patients undergoing thoracic epidural analgesia (TEA) and intra-venous patient- controlled analgesia (IV-PCA) for resection of hepatic metastatic disease.ResultsClinicopathologic variables and baseline biomarkers were similar between TEA (n = 46) and IV-PCA (n = 16) groups. Of the biomarkers which were significantly changed from baseline, there was a lower fold change from baseline in the TEA patients compared to IV-PCA including IL-6 (13.5vs19.1), MCP-1 (1.9vs3.0), IL-8 (2.4vs3.0), and Pentraxin-3 (10.8vs15.6). Overall decreased systemic concentrations of TGFb signaling were noted in TEA patients on POD1 TGFb3 (243.2 vs. 86.0, p = 0.005), POD3 TGFb1 (6558.0 vs. 2063.3, p = 0.004), POD3 TGFb2 (468.3 vs. 368.9, p = 0.036), POD3 TGFb3 (132.2 vs. 77.8, p = 0.028), and POD5 TGFb3 (306.5 vs. 92.2, p = 0.032). POD1 IL-12p70 concentrations were significantly higher in TEA patients (8.3 vs. 1.6, p = 0.024).ConclusionEpidural analgesia damped the postoperative inflammatory response and systemic immunosuppressive signaling, as well as promoted Th1 systemic signaling early in the post-operative period after hepatic resection for metastatic disease. These differences elaborate on known mechanisms for improved oncologic outcomes with regional anesthesia, and may be considered for biomarker monitoring of effective regional anesthesia in oncologic surgery.Materials and methodsPatient data, including clinicopathologic variables were collected for this study from the database of a randomized controlled trial comparing perioperative outcomes in patients undergoing hepatic resection with TEA vs. IV-PCA. Patients undergoing resection for metastatic disease were selected for this study. Plasma concentrations (pg/mL) of well-studied biomarkers (IL-1b/2/4/5/6/7/8/10/12p70/13/17, MCP-1 IFNγ, TNFα, MIP-1b, GM-CSF, G-CSF, VEGF, Resistin, TGFb1, TGFb2, and TGFb3), as well as novel perioperative markers (CXCL12, CXCL10, Omentin-1, sLeptin R, Vaspin, Pentraxin-3, Galactin-3, FGF-23, PON-1, FGF-21) were measured preoperatively, and on postoperative day (POD)1, POD3, and POD5 using multiplex bead assays. Clinicopathologic variables and perioperative variations in these biomarkers were compared between TEA vs IV-PCA groups.

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The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

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The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

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